Creation of AlkB Mutants for Protection of Bone Marrow

创建用于保护骨髓的 AlkB 突变体

• 批准号: 7253993
• 负责人: Manel Camps
• 金额: $ 13.25万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7253993
• 关键词: Address; Adenine; Adverse effects; Alkylating Agents; Alkylation; Alleles; Animal Model; Bacteriophage M13; Base Excision Repairs; Base Pairing; Biological Assay; Blood; Blood Cells; Bone Marrow; Bone Marrow Suppression; Brain Neoplasms; Bypass; Camping; Carmustine; Catalysis; Cell Line; Cells; Charge; Clinic; Clinical; Clinical Trials; Collaborations; Coupled; DNA; DNA Adducts; DNA Modification Process; Dacarbazine; Dose; Dose-Limiting; Enzymes; Escherichia coli; Evolution; Excision; Figs - dietary; Generations; Genes; Genetic Materials; Genomics; Goals; Guanine; Hematopoietic; Hemorrhage; Homologous Gene; Human; Human Cell Line; Infection; Insecta; Lesion; Libraries; Lymphoma; Mammalian Cell; Marrow; Mediating; Methylation; Modeling; Modification; Mus; Mutagenesis; Mutation; Nitrogen; O(6)-Methylguanine-DNA Methyltransferase; Performance; Pharmaceutical Preparations; Positioning Attribute; Procarbazine; Property; Proteins; Purines; Pyrimidine; Pyrimidines; Reaction; Relative (related person); Resistance; Single-Stranded DNA; Site; Soft Tissue Neoplasms; Solid; Stem cells; Substrate Specificity; Suicide; System; Testing; Toxic effect; Training; Translations; Universities; Variant; Vascular blood supply; Veterinarians; Washington; Work; adduct; base; cancer therapy; clinically relevant; comparative; cytotoxic; cytotoxicity; design; directed evolution; ds-DNA; enzyme pathway; gene therapy; improved; in vivo; killings; lexitropsin; melanoma; methyl group; methyl lexitropsin; methylpurine; mouse model; mutant; neoplastic cell; preference; protective effect; purine; repaired; temozolomide; tissue culture

DESCRIPTION (provided by applicant): Methylating agents are mainstay drugs for the treatment of cancer and are amongst the few agents available against brain tumors. Cells responsible for keeping the blood cell supply, "blood progenitor cells", are highly sensitive to these agents, which results in severe side-effects, including bleeding and infection. Blood progenitor cells can be protected from the toxic effects of methylation by resistance genes. The most effective one is AGT, which directly removes toxic modifications caused by methylation of the cell's genetic material (DNA). However, AGT does not recognize certain toxic DNA modifications. Here I propose the use of a different gene (AlkB), which targets some of these alternative lesions, to improve protection against the toxic effects of methylation. This gene, which has only recently been characterized, should therefore enhance AGT protection. Moreover, unlike AGT, AlkB remains active after mediating a repair reaction, which implies that AlkB repair should be more amenable to modulation. Here I propose a powerful approach to identify variants of one human homologue of AlkB (ABH2) with improved repair performance. Specifically, I want to enhance the enzyme's ability to recognize lesions generated by agents used in the clinic. Selected variants will be tested in human progenitor cells in culture and in a mouse animal model for protection against treatment with high doses of these agents. Ultimately, the mutants identified in this work should improve the management of side effects of methylating agents and would also allow the use of higher doses for more effective treatment.

描述（由申请人提供）：甲基化药物是治疗癌症的主要药物，也是治疗脑肿瘤的少数药物之一。